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Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury

Cell Death & Differentiation volume 32, pages 530–545 (2025)Cite this article

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Abstract

Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.

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Fig. 1: TBI increases total lactylation levels.
Fig. 2: Identification of Tufm and detection of lactylation at K286.
Fig. 3: Lactylation reduces Tufm mitochondrial distribution.
Fig. 4: Lactylation inhibits the interaction of Tufm and Tomm40.
Fig. 5: Tufm lactylation suppresses mitophagy and increases apoptosis.
Fig. 6: Tufm lactylation regulates the Tufm–Tomm40 interaction and Tufm-mediated mitophagy after TBI in vivo.
Fig. 7: Tufm lactylation regulates apoptosis and neurological functions after TBI in vivo.

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Data availability

Mass spectrometry data that support the findings of this study have been deposited in PRIDE with the accession codes PXD045802 and PXD045404. All data generated or analyzed during this study are included in this published article (and its original data file).

References

  1. Maas AIR, Menon DK, Adelson PD, Andelic N, Bell MJ, Belli A, et al. Traumatic brain injury: integrated approaches to improve prevention, clinical care, and research. Lancet Neurol. 2017;16:987–1048.

    Article  PubMed  Google Scholar 

  2. Maas AIR, Menon DK, Manley GT, Abrams M, Åkerlund C, Andelic N, et al. Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol. 2022;21:1004–60.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jiang J-Y, Gao G-Y, Feng J-F, Mao Q, Chen L-G, Yang X-F, et al. Traumatic brain injury in China. Lancet Neurol. 2019;18:286–95.

    Article  PubMed  Google Scholar 

  4. World Health Organization. Neurological disorders: public health challenges. 2006. https://www.who.int/publications/i/item/9789241563369/.

  5. Majdan M, Plancikova D, Brazinova A, Rusnak M, Nieboer D, Feigin V, et al. Epidemiology of traumatic brain injuries in Europe: a cross-sectional analysis. Lancet Public Health. 2016;1:e76–e83.

    Article  PubMed  Google Scholar 

  6. Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury-related emergency department visits, hospitalizations, and deaths - United States, 2007 and 2013. MMWR Surveill Summ. 2017;66:1–16.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Feigin VL, Theadom A, Barker-Collo S, Starkey NJ, McPherson K, Kahan M, et al. Incidence of traumatic brain injury in New Zealand: a population-based study. Lancet Neurol. 2013;12:53–64.

    Article  PubMed  Google Scholar 

  8. Corrigan F, Mander KA, Leonard AV, Vink R. Neurogenic inflammation after traumatic brain injury and its potentiation of classical inflammation. J Neuroinflammation. 2016;13:264.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fesharaki-Zadeh A. Oxidative stress in traumatic brain injury. Int J Mol Sci. 2022;23:13000.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Jamjoom AAB, Rhodes J, Andrews PJD, Grant SGN. The synapse in traumatic brain injury. Brain. 2021;144:18–31.

    Article  PubMed  Google Scholar 

  11. Hiebert JB, Shen Q, Thimmesch AR, Pierce JD. Traumatic brain injury and mitochondrial dysfunction. Am J Med Sci. 2015;350:132–8.

    Article  PubMed  Google Scholar 

  12. Nie Z, Tan L, Niu J, Wang B. The role of regulatory necrosis in traumatic brain injury. Front Mol Neurosci. 2022;15:1005422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Akamatsu Y, Hanafy KA. Cell death and recovery in traumatic brain injury. Neurotherapeutics. 2020;17:446–56.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cash A, Theus MH. Mechanisms of blood-brain barrier dysfunction in traumatic brain injury. Int J Mol Sci. 2020;21:3344.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Carpenter KLH, Jalloh I, Gallagher CN, Grice P, Howe DJ, Mason A, et al. 13C-labelled microdialysis studies of cerebral metabolism in TBI patients. Eur J Pharm Sci. 2014;57:87–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Timofeev I, Carpenter KLH, Nortje J, Al-Rawi PG, O’Connell MT, Czosnyka M, et al. Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. Brain. 2011;134:484–94.

    Article  PubMed  Google Scholar 

  17. Lozano A, Franchi F, Seastres RJ, Oddo M, Lheureux O, Badenes R, et al. Glucose and lactate concentrations in cerebrospinal fluid after traumatic brain injury. J Neurosurg Anesthesiol. 2020;32:162–9.

    Article  PubMed  Google Scholar 

  18. Thomas I, Dickens AM, Posti JP, Czeiter E, Duberg D, Sinioja T, et al. Serum metabolome associated with severity of acute traumatic brain injury. Nat Commun. 2022;13:2545.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Lai J-Q, Shi Y-C, Lin S, Chen X-R. Metabolic disorders on cognitive dysfunction after traumatic brain injury. Trends Endocrinol Metab. 2022;33:451–62.

    Article  PubMed  CAS  Google Scholar 

  20. Jiang J-Y, Xu W, Li W-P, Gao G-Y, Bao Y-H, Liang Y-M, et al. Effect of long-term mild hypothermia or short-term mild hypothermia on outcome of patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2006;26:771–6.

    Article  PubMed  Google Scholar 

  21. Hui J, Feng J, Tu Y, Zhang W, Zhong C, Liu M, et al. Safety and efficacy of long-term mild hypothermia for severe traumatic brain injury with refractory intracranial hypertension (LTH-1): a multicenter randomized controlled trial. EClinicalMedicine. 2021;32:100732.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Maxwell WL, Donnelly S, Sun X, Fenton T, Puri N, Graham DI. Axonal cytoskeletal responses to nondisruptive axonal injury and the short-term effects of posttraumatic hypothermia. J Neurotrauma. 1999;16:1225–34.

    Article  PubMed  CAS  Google Scholar 

  23. Koizumi H, Povlishock JT. Posttraumatic hypothermia in the treatment of axonal damage in an animal model of traumatic axonal injury. J Neurosurg. 1998;89:303–9.

    Article  PubMed  CAS  Google Scholar 

  24. Marion DW, White MJ. Treatment of experimental brain injury with moderate hypothermia and 21-aminosteroids. J Neurotrauma. 1996;13:139–47.

    Article  PubMed  CAS  Google Scholar 

  25. Yang K, Fan M, Wang X, Xu J, Wang Y, Tu F, et al. Lactate promotes macrophage HMGB1 lactylation, acetylation, and exosomal release in polymicrobial sepsis. Cell Death Differ. 2022;29:133–46.

    Article  PubMed  CAS  Google Scholar 

  26. Pucino V, Cucchi D, Mauro C. Lactate transporters as therapeutic targets in cancer and inflammatory diseases. Expert Opin Ther Targets. 2018;22:735–43.

    Article  PubMed  CAS  Google Scholar 

  27. Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Liu X, Zhang Y, Li W, Zhou X. Lactylation, an emerging hallmark of metabolic reprogramming: current progress and open challenges. Front Cell Dev Biol. 2022;10:972020.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Raghupathi R, Graham DI, McIntosh TK. Apoptosis after traumatic brain injury. J Neurotrauma. 2000;17:927–38.

    Article  PubMed  CAS  Google Scholar 

  30. Zhang X, Chen Y, Jenkins LW, Kochanek PM, Clark RSB. Bench-to-bedside review: apoptosis/programmed cell death triggered by traumatic brain injury. Crit Care. 2005;9:66–75.

    Article  PubMed  CAS  Google Scholar 

  31. Raghupathi R. Cell death mechanisms following traumatic brain injury. Brain Pathol. 2004;14:215–22.

    Article  PubMed  Google Scholar 

  32. He Z, Lang L, Hui J, Ma Y, Yang C, Weng W, et al. Brain extract of subacute traumatic brain injury promotes the neuronal differentiation of human neural stem cells via autophagy. J Clin Med. 2022;11:2709.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Sarkar C, Zhao Z, Aungst S, Sabirzhanov B, Faden AI, Lipinski MM. Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury. Autophagy. 2014;10:2208–22.

    Article  PubMed  CAS  Google Scholar 

  34. Lin C, Chao H, Li Z, Xu X, Liu Y, Hou L, et al. Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy. J Pineal Res. 2016;61:177–86.

    Article  PubMed  CAS  Google Scholar 

  35. Scrivo A, Bourdenx M, Pampliega O, Cuervo AM. Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol. 2018;17:802–15.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013;20:31–42.

    Article  PubMed  CAS  Google Scholar 

  37. Wu Q, Gao C, Wang H, Zhang X, Li Q, Gu Z, et al. Mdivi-1 alleviates blood-brain barrier disruption and cell death in experimental traumatic brain injury by mitigating autophagy dysfunction and mitophagy activation. Int J Biochem Cell Biol. 2018;94:44–55.

    Article  PubMed  CAS  Google Scholar 

  38. Ren Y-Z, Zhang B-Z, Zhao X-J, Zhang Z-Y. Resolvin D1 ameliorates cognitive impairment following traumatic brain injury via protecting astrocytic mitochondria. J Neurochem. 2020;154:530–46.

    Article  PubMed  CAS  Google Scholar 

  39. Lin C, Li N, Chang H, Shen Y, Li Z, Wei W, et al. Dual effects of thyroid hormone on neurons and neurogenesis in traumatic brain injury. Cell Death Dis. 2020;11:671.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Ma J, Ni H, Rui Q, Liu H, Jiang F, Gao R, et al. Potential roles of NIX/BNIP3L pathway in rat traumatic brain injury. Cell Transplant. 2019;28:585–95.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chao H, Lin C, Zuo Q, Liu Y, Xiao M, Xu X, et al. Cardiolipin-dependent mitophagy guides outcome after traumatic brain injury. J Neurosci. 2019;39:1930–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Wang R, Zhu Y, Ren C, Yang S, Tian S, Chen H, et al. Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. Autophagy. 2021;17:496–511.

    Article  PubMed  CAS  Google Scholar 

  43. Wang K, Ma H, Liu H, Ye W, Li Z, Cheng L, et al. The glycoprotein and nucleocapsid protein of hantaviruses manipulate autophagy flux to restrain host innate immune responses. Cell Rep. 2019;27:2075–91.e5.

    Article  PubMed  CAS  Google Scholar 

  44. Ding B, Zhang L, Li Z, Zhong Y, Tang Q, Qin Y, et al. The matrix protein of human parainfluenza virus type 3 induces mitophagy that suppresses interferon responses. Cell Host Microbe. 2017;21:538–47.e4.

    Article  PubMed  CAS  Google Scholar 

  45. Choi C-Y, Vo MT, Nicholas J, Choi YB. Autophagy-competent mitochondrial translation elongation factor TUFM inhibits caspase-8-mediated apoptosis. Cell Death Differ. 2022;29:451–64.

    Article  PubMed  CAS  Google Scholar 

  46. Lai F-L, Gao F. Auto-Kla: a novel web server to discriminate lysine lactylation sites using automated machine learning. Brief Bioinform. 2023;24:bbad070.

    Article  PubMed  Google Scholar 

  47. Araiso Y, Tsutsumi A, Qiu J, Imai K, Shiota T, Song J, et al. Structure of the mitochondrial import gate reveals distinct preprotein paths. Nature. 2019;575:395–401.

    Article  PubMed  CAS  Google Scholar 

  48. Araiso Y, Imai K, Endo T. Role of the TOM complex in protein import into mitochondria: structural views. Annu Rev Biochem. 2022;91:679–703.

    Article  PubMed  CAS  Google Scholar 

  49. Gabriel K, Egan B, Lithgow T. Tom40, the import channel of the mitochondrial outer membrane, plays an active role in sorting imported proteins. EMBO J. 2003;22:2380–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Hagihara H, Shoji H, Otabi H, Toyoda A, Katoh K, Namihira M, et al. Protein lactylation induced by neural excitation. Cell Rep. 2021;37:109820.

    Article  PubMed  CAS  Google Scholar 

  51. Dai S-K, Liu P-P, Li X, Jiao L-F, Teng Z-Q, Liu C-M. Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development. Development. 2022;149:dev200049.

    Article  PubMed  CAS  Google Scholar 

  52. Pan R-Y, He L, Zhang J, Liu X, Liao Y, Gao J, et al. Positive feedback regulation of microglial glucose metabolism by histone H4 lysine 12 lactylation in Alzheimer’s disease. Cell Metab. 2022;34:634–48.e6.

    Article  PubMed  CAS  Google Scholar 

  53. Yao Y, Bade R, Li G, Zhang A, Zhao H, Fan L, et al. Global-scale profiling of differential expressed lysine-lactylated proteins in the cerebral endothelium of cerebral ischemia-reperfusion injury rats. Cell Mol Neurobiol. 2022;43:1989–2004.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Carpenter KLH, Jalloh I, Hutchinson PJ. Glycolysis and the significance of lactate in traumatic brain injury. Front Neurosci. 2015;9:112.

    Article  PubMed  PubMed Central  Google Scholar 

  55. McGinn MJ, Povlishock JT. Pathophysiology of traumatic brain injury. Neurosurg Clin N Am. 2016;27:397–407.

    Article  PubMed  Google Scholar 

  56. Pellerin L, Magistretti PJ. Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA. 1994;91:10625–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Glenn TC, Martin NA, Horning MA, McArthur DL, Hovda DA, Vespa P, et al. Lactate: brain fuel in human traumatic brain injury: a comparison with normal healthy control subjects. J Neurotrauma. 2015;32:820–32.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Patel AB, Lai JCK, Chowdhury GMI, Hyder F, Rothman DL, Shulman RG, et al. Direct evidence for activity-dependent glucose phosphorylation in neurons with implications for the astrocyte-to-neuron lactate shuttle. Proc Natl Acad Sci USA. 2014;111:5385–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Glenn TC, Kelly DF, Boscardin WJ, McArthur DL, Vespa P, Oertel M, et al. Energy dysfunction as a predictor of outcome after moderate or severe head injury: indices of oxygen, glucose, and lactate metabolism. J Cereb Blood Flow Metab. 2003;23:1239–50.

    Article  PubMed  CAS  Google Scholar 

  60. Dienel GA. The metabolic trinity, glucose-glycogen-lactate, links astrocytes and neurons in brain energetics, signaling, memory, and gene expression. Neurosci Lett. 2017;637:18–25.

    Article  PubMed  CAS  Google Scholar 

  61. Jiang J-Y, Liang Y-M, Luo Q-Z, Zhu C. Effect of mild hypothermia on brain dialysate lactate after fluid percussion brain injury in rodents. Neurosurgery. 2004;54:713–7.

    Article  PubMed  Google Scholar 

  62. Zhao Q-J, Zhang X-G, Wang L-X. Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. J Crit Care. 2011;26:311–5.

    Article  PubMed  CAS  Google Scholar 

  63. Sharma NK, Pal JK. Metabolic ink lactate modulates epigenomic landscape: a concerted role of pro-tumor microenvironment and macroenvironment during carcinogenesis. Curr Mol Med. 2021;21:177–81.

    Article  PubMed  CAS  Google Scholar 

  64. Kalgudi S, Ho KM. Incidence of antithrombin deficiency and anti-cardiolipin antibodies after severe traumatic brain injury: a prospective cohort study. Neurocrit Care. 2021;34:227–35.

    Article  PubMed  CAS  Google Scholar 

  65. Saw MM, Chamberlain J, Barr M, Morgan MPG, Burnett JR, Ho KM. Differential disruption of blood-brain barrier in severe traumatic brain injury. Neurocrit Care. 2014;20:209–16.

    Article  PubMed  CAS  Google Scholar 

  66. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol. 2013;15:1197–205.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Tian C, Min X, Zhao Y, Wang Y, Wu X, Liu S, et al. MRG15 aggravates non-alcoholic steatohepatitis progression by regulating the mitochondrial proteolytic degradation of TUFM. J Hepatol. 2022;77:1491–503.

    Article  PubMed  CAS  Google Scholar 

  68. Xu X, Huang A, Cui X, Han K, Hou X, Wang Q, et al. Ubiquitin specific peptidase 5 regulates colorectal cancer cell growth by stabilizing Tu translation elongation factor. Theranostics. 2019;9:4208–20.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Wei R, Lv X, Fang C, Liu C, Ma Z, Liu K. Silencing TUFM inhibits development of monocrotaline-induced pulmonary hypertension by regulating mitochondrial autophagy via AMPK/mTOR signal pathway. Oxid Med Cell Longev. 2022;2022:4931611.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Wu X, Xu M, Geng M, Chen S, Little PJ, Xu S, et al. Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies. Signal Transduct Target Ther. 2023;8:220.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Lin J, Chen K, Chen W, Yao Y, Ni S, Ye M, et al. Paradoxical mitophagy regulation by PINK1 and TUFm. Mol Cell. 2020;80:607–20.e12.

    Article  PubMed  CAS  Google Scholar 

  72. Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, et al. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell. 2013;50:919–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Ma X, Aravind A, Pfister BJ, Chandra N, Haorah J. Animal models of traumatic brain injury and assessment of injury severity. Mol Neurobiol. 2019;56:5332–45.

    Article  PubMed  CAS  Google Scholar 

  74. Siebold L, Obenaus A, Goyal R. Criteria to define mild, moderate, and severe traumatic brain injury in the mouse controlled cortical impact model. Exp Neurol. 2018;310:48–57.

    Article  PubMed  Google Scholar 

  75. Flierl MA, Stahel PF, Beauchamp KM, Morgan SJ, Smith WR, Shohami E. Mouse closed head injury model induced by a weight-drop device. Nat Protoc. 2009;4:1328–37.

    Article  PubMed  CAS  Google Scholar 

  76. Shan H-M, Maurer MA, Schwab ME. Four-parameter analysis in modified rotarod test for detecting minor motor deficits in mice. BMC Biol. 2023;21:177.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Gong W, Das S, Sierra-Pagan JE, Skie E, Dsouza N, Larson TA, et al. ETV2 functions as a pioneer factor to regulate and reprogram the endothelial lineage. Nat Cell Biol. 2022;24:672–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Sciarretta C, Minichiello L. The preparation of primary cortical neuron cultures and a practical application using immunofluorescent cytochemistry. Methods Mol Biol. 2010;633:221–31.

    Article  PubMed  CAS  Google Scholar 

  79. Ji J, Kline AE, Amoscato A, Samhan-Arias AK, Sparvero LJ, Tyurin VA, et al. Lipidomics identifies cardiolipin oxidation as a mitochondrial target for redox therapy of brain injury. Nat Neurosci. 2012;15:1407–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Weng W, Gu X, Yang Y, Zhang Q, Deng Q, Zhou J, et al. N-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization. Nat Commun. 2023;14:5688.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Liu H, Weng W, Guo R, Zhou J, Xue J, Zhong S, et al. Olig2 SUMOylation protects against genotoxic damage response by antagonizing p53 gene targeting. Cell Death Differ. 2020;27:3146–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Ma R, Ma L, Weng W, Wang Y, Liu H, Guo R, et al. DUSP6 SUMOylation protects cells from oxidative damage via direct regulation of Drp1 dephosphorylation. Sci Adv. 2020;6:eaaz0361.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

The authors acknowledge the use of Biorender.com which is used to create the schematic model in Supplementary Information, Fig. S7.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82071358 and 82371379 to JF, 82372501 to JJ, 82401610 to W Weng), the Program of Shanghai Academic Research Leader (21XD1422400 to JF), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Support (02.101005.001.30.30A to JF), and the Project of Shanghai Medical And Health Development Foundation (20224Z0012 to JF).

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  1. These authors contributed equally: Weiji Weng, Zhenghui He, Zixuan Ma, Jialin Huang, Yuhan Han.

Authors and Affiliations

  1. Brain Injury Centre, Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Weiji Weng, Zhenghui He, Zixuan Ma, Yuhan Han, Qiyuan Feng, Wenlan Qi, Yidong Peng, Jiangchang Wang, Jiacheng Gu, Wenye Wang, Jiyao Jiang & Junfeng Feng

  2. Shanghai Institute of Head Trauma, Shanghai, China

    Weiji Weng, Zhenghui He, Zixuan Ma, Jialin Huang, Yuhan Han, Qiyuan Feng, Wenlan Qi, Yidong Peng, Jiangchang Wang, Jiacheng Gu, Wenye Wang, Yong Lin, Jiyao Jiang & Junfeng Feng

  3. Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Weiji Weng

  4. Department of Pharmacology and Chemical Biology, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jialin Huang & Gan Jiang

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Contributions

JF and W Weng conceived the study and designed the experiments. W Weng, ZH, ZM, JH and YH carried out the experiments. QF and WQ assisted with data analysis and analyzed the results. YP, JW, JG, W Wang, YL, JJ, GJ, W Weng and JF discussed the results. W Weng, ZH and JF wrote the manuscript. W Weng, JH, JJ and JF reviewed/edited the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Junfeng Feng.

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The authors declare no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations. All animal experiments were conducted in agreement with the Guide for the Care and Use of Laboratory Animals and approved by the Institutional Animal Care and Use Committee of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine (Reference No. 2023-106). This study related to patients has been approved by the Ethics Committee of Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine (Reference No. LY2023-017-B). The informed consent was obtained from all participants.

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Weng, W., He, Z., Ma, Z. et al. Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury. Cell Death Differ 32, 530–545 (2025). https://doi.org/10.1038/s41418-024-01408-0

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